Short and Efficient Synthesis of Cryptophycin Unit A

Abstract

[reaction: see text] Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality, while all further stereogenic centers are introduced under substrate control. The key step of the first route is a vinylogous Mukaiyama aldol addition, which introduces the alpha,beta-unsaturated ester moiety with defined configuration at the delta-carbon atom. Likewise, allylation with allyltributylstannane diastereoselectively gives the homoallylic alcohol that can be converted by a metathesis reaction to a unit A precursor.

Total synthesis and biological evaluation of fluorinated cryptophycins

“…The synthesis of the para -trifluoromethyl substituted unit A started with a modified Knoevenagel condensation [23,31]. The required aldehyde 9 was obtained by DIBAL-H reduction of the corresponding methyl ester 8 and was found to decompose upon chromatographic purification (Scheme 1).…”

“…The latter compound was transformed into the methyl ester by treatment with SOCl 2 in methanol. The resulting ester 11 could then be directly employed without purification in the asymmetric dihydroxylation with osmium tetroxide and (DHQD) 2 PHAL, in close analogy to a previously published procedure [23]. The initially formed vicinal diol cyclizes under the reaction conditions to give lactone 12 in enantiomerically pure form (chiral HPLC: Chiralpak OD ® ).…”

“…In the frame of our on-going SAR studies on cryptophycins [19,23–30], we envisaged the synthesis of analogues of cryptophycin-52 with a para -trifluoromethyl substituent at the unit A aryl ring. In addition, we targeted the replacement of the unit B by a D-pentafluorophenylalanine residue.…”

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…The authors used the Helmchen-Yamamoto [17][18][19] extended Corey [20] catalyst (25) in an enantioselective VMAR toward the total synthesis of angiolam A (31) (Scheme 2.7) [21].…”

“…Two challenging examples have been explored in the context of the total syntheses of (+)-ratjadone (35) required to establish the desired stereochemical relationship at C3 later on (not shown). A short and efficient synthesis of polyketide subunit 42 of cryptophycin-1 was performed using magnesium bromide diethyl etherate mediated VMAR of (E,Z)-(1-tert-butoxybuta-1,3-dienyloxy)trimethylsilane (40) to aldehyde 41 (Scheme 2.10) [25]. Taking advantage of a chelation-controlled transition state fragment 42 was isolated in moderate yield but with excellent diastereoselection (95% de).…”